8-144424072-C-T

Variant names:

• chr8-144424072-C-T
• rs371861006
• NM_016208.4:c.517G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016208.4(VPS28):​c.517G>A​(p.Asp173Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000396 in 1,566,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: VPS28 NM_016208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 publications found

Genes affected

VPS28 (HGNC:18178): (VPS28 subunit of ESCRT-I) This gene encodes a protein subunit of the ESCRT-I complex (endosomal complexes required for transport), which functions in the transport and sorting of proteins into subcellular vesicles. This complex can also be hijacked to facilitate the budding of enveloped viruses from the cell membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37470955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	NM_016208.4	MANE Select	c.517G>A	p.Asp173Asn	missense	Exon 9 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.517G>A	p.Asp173Asn	missense	Exon 9 of 9	NP_898880.1	Q9UK41-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	ENST00000292510.6	TSL:1 MANE Select	c.517G>A	p.Asp173Asn	missense	Exon 9 of 10	ENSP00000292510.3	Q9UK41-1
	VPS28	ENST00000377348.6	TSL:1	c.517G>A	p.Asp173Asn	missense	Exon 9 of 9	ENSP00000366565.2	Q9UK41-2
	VPS28	ENST00000526054.5	TSL:1	c.517G>A	p.Asp173Asn	missense	Exon 8 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000276 AC: 6 AN: 217686 AF XY: 0.0000432

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.000383

GnomAD4 exome AF: 0.0000396 AC: 56 AN: 1414424 Hom.: 0 Cov.: 29 AF XY: 0.0000459 AC XY: 32 AN XY: 696826

African (AFR) AF: 0.00 AC: 0 AN: 32670

American (AMR) AF: 0.00 AC: 0 AN: 41636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22902

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39144

South Asian (SAS) AF: 0.0000508 AC: 4 AN: 78808

European-Finnish (FIN) AF: 0.0000395 AC: 2 AN: 50588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.0000424 AC: 46 AN: 1084820

Other (OTH) AF: 0.0000514 AC: 3 AN: 58320

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000861 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Benign	0.082	T
Sift4G	Benign	0.12	T
Polyphen		0.37	B
Vest4		0.57
MVP		0.22
MPC		0.027
ClinPred		0.45	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.79
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371861006; hg19: chr8-145649455;